A critical question for understanding development and disease is to reveal how external signals modulate the cell cycle and how certain cells (tumor and stem cells) escape such stop signals. The goal of this proposal is to investigate how the developmental control of cell cycle state is brought about by action of context specific pathways on general cell cycle machinery. We will use two important models of developmentally controlled cell division: the mitotic-to-endocycle transition in epithelial cells and the continuous cell division of stem cells. Our laboratory has recently revealed the key developmental regulators of the cell cycle in these two systems: first, the master regulator Notch is required for the mitotic to- endocycle transition and second, the microRNA pathway is critical in making stem cells resistant to cell cycle stop signals. We now propose to analyze how this regulation takes place at the molecular level. In both cases we seek first to understand how the key regulators get activated for the purpose of cell cycle regulation and second, how the canonical pathways impact the cell cycle machinery.